WASH knockout T cells demonstrate defective receptor trafficking, proliferation, and effector function

Joshua T. Piotrowski, Timothy S. Gomez, Renee A. Schoon, Ashutosh K. Mangalam, Daniel D Billadeau

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

WASH is an Arp2/3 activator of the Wiskott-Aldrich syndrome protein superfamily that functions during endosomal trafficking processes in collaboration with the retromer and sorting nexins, but its in vivo function has not been examined. To elucidate the physiological role of WASH in T cells, we generated a WASH conditional knockout (WASHout) mouse model. Using CD4Cre deletion, we found that thymocyte development and naive T cell activation are unaltered in the absence of WASH. Surprisingly, despite normal T cell receptor (TCR) signaling and interleukin-2 production, WASHout T cells demonstrate significantly reduced proliferative potential and fail to effectively induce experimental autoimmune encephalomyelitis. Interestingly, after activation, WASHout T cells fail to maintain surface levels of TCR, CD28, and LFA-1. Moreover, the levels of the glucose transporter, GLUT1, are also reduced compared to wild-type T cells. We further demonstrate that the loss of surface expression of these receptors in WASHout cells results from aberrant accumulation within the collapsed endosomal compartment, ultimately leading to degradation within the lysosome. Subsequently, activated WASHout T cells experience reduced glucose uptake and metabolic output. Thus, we found that WASH is a newly recognized regulator of TCR, CD28, LFA-1, and GLUT1 endosome-to-membrane recycling. Aberrant trafficking of these key T cell proteins may potentially lead to attenuated proliferation and effector function.

Original languageEnglish (US)
Pages (from-to)958-973
Number of pages16
JournalMolecular and Cellular Biology
Volume33
Issue number5
DOIs
StatePublished - Mar 2013

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T-Lymphocytes
T-Cell Antigen Receptor
Lymphocyte Function-Associated Antigen-1
Sorting Nexins
Wiskott-Aldrich Syndrome Protein
Autoimmune Experimental Encephalomyelitis
Facilitative Glucose Transport Proteins
Endosomes
Thymocytes
Lysosomes
Knockout Mice
Interleukin-2
Glucose
Membranes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

WASH knockout T cells demonstrate defective receptor trafficking, proliferation, and effector function. / Piotrowski, Joshua T.; Gomez, Timothy S.; Schoon, Renee A.; Mangalam, Ashutosh K.; Billadeau, Daniel D.

In: Molecular and Cellular Biology, Vol. 33, No. 5, 03.2013, p. 958-973.

Research output: Contribution to journalArticle

Piotrowski, Joshua T. ; Gomez, Timothy S. ; Schoon, Renee A. ; Mangalam, Ashutosh K. ; Billadeau, Daniel D. / WASH knockout T cells demonstrate defective receptor trafficking, proliferation, and effector function. In: Molecular and Cellular Biology. 2013 ; Vol. 33, No. 5. pp. 958-973.
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